title: Molecular dynamics simulations of forced unbending of integrin α(v)β₃.
abstract: Integrins may undergo large conformational changes during activation, but the dynamic processes and pathways remain poorly understood. We used molecular dynamics to simulate forced unbending of a complete integrin α(v)β₃ ectodomain in both unliganded and liganded forms. Pulling the head of the integrin readily induced changes in the integrin from a bent to an extended conformation. Pulling at a cyclic RGD ligand bound to the integrin head also extended the integrin, suggesting that force can activate integrins. Interactions at the interfaces between the hybrid and β tail domains and between the hybrid and epidermal growth factor 4 domains formed the major energy barrier along the unbending pathway, which could be overcome spontaneously in ~1 µs to yield a partially-extended conformation that tended to rebend. By comparison, a fully-extended conformation was stable. A newly-formed coordination between the α(v) Asp457 and the α-genu metal ion might contribute to the stability of the fully-extended conformation. These results reveal the dynamic processes and pathways of integrin conformational changes with atomic details and provide new insights into the structural mechanisms of integrin activation.
authors.affiliation: Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States of America.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Jizhong
authors.initials: J
authors.lastname: Lou
authors.forename: Jen
authors.initials: J
authors.lastname: Hsin
authors.forename: Klaus
authors.initials: K
authors.lastname: Schulten
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Harvey
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhu
mesh_terms: D006801:Humans; D039302:Integrin alphaVbeta3 / Q000737:chemistry* / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D009842:Oligopeptides / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D055550:Protein Stability; D017434:Protein Structure, Tertiary
chemical_list: D039302:Integrin alphaVbeta3; D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid